| Description |
En anglais
«Translating from Animal Models to Human Schizophrenia:
Insights into Pathophysiology, Treatment and Prevention»
Résumé :
There
is considerable evidence that schizophrenia involves a dysregulated dopamine
system, potentially driven by overactivity in the hippocampus. Furthermore,
multiple postmortem studies of schizophrenia brains show a substantial loss of
a particular type of inhibitory neuron known as the parvalbumin GABAergic
interneuron; loss of this neuron is thought to drive the hippocampal
hyperactivity and dysrhythmic activity, leading to an over-responsive dopamine
system. Our studies suggest that when the hippocampus is hyperactive and
dysrhythmic, the dopamine system is hyper-responsive to stimuli, which can
underlie the resultant hallucinations and delusions. A major question is why
there is interneuron loss in the hippocampus. Parvalbumin interneurons early in
life are susceptible to damage due to stress. In a developmental disruption
model of schizophrenia in the rat, we found that prepubertally these rats are
hyper-responsive to stress, and furthermore relieving the stress early in life
prevents the transition to “psychosis” in adulthood. This suggests that
schizophrenia susceptibility may be due to heightened sensitivity to the
deleterious effects of stress. Indeed, multiple stressors given during this
sensitive period to normal rats can lead to the schizophrenia phenotype.
Moreover, elimination of the ability of the medial prefrontal cortex to
regulate stress makes normal rats hypersensitive to stressors that would not
impact an intact rat. Given that identical twins are concordant for
schizophrenia only 50% of the time, and that as much as half of schizophrenia
is not familial, this leads to the intriguing possibility that genetic
predisposition does not cause schizophrenia, but instead like the developmental
disruption model causes the individual to be hypersensitive to the deleterious
effects of stress. Therefore, controlling stress early in life in susceptible
individuals may be an effective means to prevent transition to schizophrenia later
in life.
Dr. Anthony A. Grace is a Distinguished Professor of Neuroscience and a
Professor of Psychiatry and Psychology at the University of Pittsburgh in
Pittsburgh, PA. He received his Ph.D. from Yale University School of Medicine
with Dr. Benjamin S. Bunney and had postdoctoral training with Dr. Rodolfo
Llinas in the Department of Physiology and Biophysics at New York University
School of Medicine. Dr. Grace has been involved in translational research
related to the dopamine system for over 30 years. His early work pioneered the
mode of action of antipsychotic drugs, and the identification and
characterization of dopamine-containing neurons, and was the first to provide a
means to quantify their activity state and pattern in a way that is the
standard in the literature. His current work involves novel treatments for
schizophrenia and its prevention, the role of dopamine in anhedonia and
affective disorders, and the mode of action of ketamine and novel
antidepressant drugs. Dr. Grace has received several awards for his research,
including the William K. Warren Award for Excellence in Schizophrenia Research,
the Efron Award and the Axelrod Award from the American College of
Neuropsychopharmacology, the Gold Medal award from the Society of Biological
Psychiatry, the Outstanding Basic Research award from the Schizophrenia
International Research Society, as well as a NIMH MERIT award, and a
Distinguished Investigator award from the National Alliance for Research in
Schizophrenia and Depression. He is on the editorial board for numerous leading
journals in the field. Dr. Grace has made a substantial impact on the field,
publishing more than 280 articles (H index 89) spanning basic and clinical
research, and has been cited nearly 30,000 times. He is one of a
handful of individuals that not only performs important basic research, but can
integrate this work into testable models relevant to the human condition.
http://www.pitt.edu/~graceaa
Key publications:
Gomes,
F.V. and Grace, A.A. (2016) Prefrontal cortex dysfunction increases
susceptibility to schizophrenia-like changes induced by adolescent stress
exposure. Schizophrenia Bulletin (in press)
Du,
Y. and Grace, A.A. (2016) Loss of parvalbumin interneurons in the hippocampus of
MAM schizophrenia model rats is attenuated by peripubertal diazepam.
International Journal of Neuropsychopharmacology doi: 10.1093/ijnp/pyw065.
PMID: 27432008
Grace,
A.A. (2016) Dysregulation of the dopamine system in the pathophysiology of
schizophrenia and depression. Nature Neuroscience Reviews 17: 524-532.
http://dx.doi.org/10.1038/nrn.2016.57. PMID: 27256556
Gomes,
F.V., Rincon-Cortes, M. and Grace, A.A. (2016) Adolescence as a period of
vulne- rability and intervention in schizophrenia: Insights from the MAM model.
Neuroscience and Biobehavioral Reviews 70: 260-270.
doi:10.1016/j.neubiorev.2016.05.030. PMC5074867.
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